Summary of Work: The mechanisms involved in the initiation, progression and maturation of atherosclerotic plaques have previously been characterized by risk factor exposure leading to endothelial injury, followed by lipid deposition, and inflammatory cell migration. These events produce vascular changes that eventually result in intraluminal thrombosis, strokes and heart attacks. However, despite the presence of these prerequisite vascular changes, not all atherosclerotic plaques result in thrombotic or thromboembolic events, and the overall morphologic and cellular differences have been inconsistent indices for predicting plaque conversion to a symptomatic or pro-thrombotic state. Recent studies have focused on the role of immune mediators and inflammation in the destabilization of atherosclerotic plaque. We have hypothesized that inflammatory processes within the body of the plaque result in the conversion of the overlying endothelium to a proinflammatory and prothrombotic state. We have further hypothesized that circulating leukocytes would reflect the proinflammatory nature of activated endothelium and express a higher concentration of adhesion molecule ligands. And finally, inflammatory and anti-inflammatory profiles in the peripheral blood will correlate with symptomatic atherosclerotic activity. To test these hypotheses we examined carotid plaques and blood from humans undergoing carotid endarterectomy (CEA) for symptomatic, i.e. TIA's or stroke, and asymptomatic atherosclerotic disease. We found a 2-fold increase in intercellular adhesion molecule-1 (ICAM-1) immunoreactivity on the endothelial surface of atherosclerotic plaques from symptomatic vs asymptomatic patients. We further found plasma soluble ICAM-1 levels to be elevated in the patients with atherosclerosis vs age-matched controls. Leukocytes from symptomatic patients were found to have a significant increase in membrane expression of the adhesion molecule ligand, MAC-1, by flow cytometry compared to asymptomatic patients. Finally, IL-1ra, theorized to be a systemic, anti-inflammatory response to activated endothelium, is significantly elevated in patients who have symptomatic atherosclerotic plaques. This profile of results suggests that plaque conversion from an asymptomatic to a symptomatic state that causes thrombotic or thromboembolic events is associated with activation of inflammatory processes. Current studies are focusing on genetic regulators of inflammation (i.e., gene polymorphisms in families of cytokines) which may account for the wide variance in leukocyte activation and increased cytokine expression in patients with similar risk factor exposure. Future studies will address the mechanisms within the plaque that lead to an increased level of inflammation with the aim of future modification.